Ameloblastoma (AM), a locally aggressive odontogenic tumor, exhibits elusive pathogenesis. Here, optic atrophy 1 (OPA1)-mediated mitochondrial hyperfusion was identified as a driver of tumor stemness and progression. Single-cell transcriptomics of primary AM specimens revealed mitochondrial fusion^High epithelial subpopulations exhibiting enriched stemness pathways. A striking up-regulation of OPA1 was observed in AM tissues, establishing a robust correlation between elevated OPA1 expression and up-regulated stemness markers, whereas functional experiments demonstrated that OPA1 overexpression amplifies self-renewal capacity and invasive aggression in human telomerase reverse transcriptase (hTERT)⁺-AM cells. Mechanistically, mitochondrial hyperfusion suppresses Hippo signaling, enabling yes-associated protein 1 (YAP1) nuclear translocation and TEA domain transcription factor (TEAD)-dependent transcription. OPA1-overexpressing cells exhibited robust nuclear YAP1 enrichment, driving stem-like expansion. Critically, clinical analysis established OPA1^High tumors as having elevated growth rates, consolidating mitochondrial hyperfusion as a prognostic determinant. Therapeutically, MYLS22-a first-in-class OPA1 inhibitor-suppressed mitochondrial hyperfusion and reduced stemness in patient-derived organoids. The present work unveils an OPA1-mediated mitochondrial fusion-YAP1 nuclear translocation axis as the cornerstone of AM stemness, proposing OPA1 as a druggable target for this recalcitrant tumor.

2025-10-17·Science Advances

Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia

Article

作者: Avrampou, Kleopatra ; Gritsman, Kira ; Ames, Kristina ; Glytsou, Christina ; Witkowski, Matthew T. ; Pellattiero, Anna ; Scorrano, Luca ; La Vecchia, Sofia ; Antonoglou, Petros ; Magrin, Federico ; Su, Xiaoyang ; Aifantis, Iannis ; Doshi, Saurav ; Mattarei, Andrea ; Kundu, Tanima ; Verma, Amit ; Al Santli, Wafa

Acute myeloid leukemia (AML) is the most prevalent and deadliest adult leukemia. Its frontline treatment uses the BH3 mimetic venetoclax to trigger mitochondria-dependent apoptosis. However, drug resistance nearly always develops, calling for therapies to circumvent it. Advanced microscopy and genome-wide CRISPRi screen analyses pinpointed mitochondrial adaptations primarily mediated by the master regulator of cristae shape optic atrophy 1 (OPA1) as critical for BH3 mimetics resistance. Resistant AML cells up-regulate OPA1 to modify their mitochondrial structure and evade apoptosis. MYLS22 and Opitor-0, two specific and nontoxic OPA1 inhibitors, promote apoptotic cristae remodeling and cytochrome c release, synergizing with venetoclax in AML cells and xenografts derived from AML patients ex vivo and in vivo. Mechanistically, OPA1 loss renders AML cells dependent on glutamine and sensitizes them to ferroptosis by activating ATF4-regulated integrated stress responses. Overall, our data clarify how OPA1 up-regulation allows AML cells' metabolic flexibility and survival and nominates specific OPA1 inhibitors as efficacious tools to overcome venetoclax resistance in leukemia.

2025-10-01·JOURNAL OF NEUROIMMUNOLOGY

OPA1 modulates NLRP3 inflammasome activation and microglial-mediated neuroinflammation in neonatal hypoxic-ischemic brain injury

Article

作者: Jin, Ye ; Shen, Haiyan ; Lv, Qingchen ; Sun, Zhanyuan ; Mao, Liming ; Song, Lei ; Hong, Fei ; Lu, Hongyi

BACKGROUND:

Hypoxic-ischemic brain injury (HIBD) represents a primary cause of neurological impairment in neonates and is frequently associated with persistent cognitive and motor deficits. This study explores the regulatory function of optic atrophy 1 (OPA1) in modulating NLRP3 inflammasome-mediated neuroinflammation in a neonatal rat model of hypoxic-ischemic encephalopathy (HIE), and evaluates the impact of the OPA1 inhibitor MYLS22 on neuroinflammatory responses and cerebral injury.

METHODS:

Neonatal rats were subjected to HIBD. Temporal expression patterns of OPA1 and inflammasome-associated proteins were assessed using Western blotting, immunofluorescence, and histopathological analyses. The influence of MYLS22 treatment on neuroinflammatory markers, brain pathology, and cognitive outcomes was also investigated.

RESULT:

HIBD led to a marked reduction in long-form OPA1 (L-OPA1) expression and a concomitant increase in short-form OPA1 (S-OPA1). Activation of the NLRP3 inflammasome peaked between 24 and 48 h post-injury. Treatment with MYLS22 suppressed OPA1 expression in a dose-dependent manner, further enhancing inflammasome activation and aggravating brain injury, characterized by enlarged infarct volumes, increased edema, and impaired cognitive performance. Conversely, in vitro overexpression of L-OPA1 attenuated inflammasome activation and reduced microglial inflammation following ischemia/reperfusion insult, indicating a neuroprotective effect.

CONCLUSION:

These findings demonstrate a pivotal role for OPA1 in controlling neuroinflammation and mitochondrial integrity in the context of HIE. Modulation of OPA1 expression or targeting inflammasome signaling may represent promising therapeutic strategies to alleviate neuroinflammatory injury and improve neurological outcomes in neonates.

项与 MYLS-22 相关的新闻（医药）

2025-11-16

·奇点网

《科学·进展》：囚禁“死神”？科学家发现，白血病细胞通过蛋白质OPA1重塑线粒体，囚禁凋亡诱导因子，逃避维奈克拉引发的死亡

*仅供医学专业人士阅读参考急性髓系白血病（AML），这种最常见的成人白血病，以其高致死率让医生和科学家们倍感棘手。尽管以维奈克拉为代表的BH3模拟物（通过靶向BCL-2蛋白诱导线粒体依赖性凋亡）已成为一线治疗，但“道高一尺，魔高一丈”，耐药性几乎总会发生，成为治愈之路上的巨大拦路虎。当科学家们深入探究肿瘤细胞如何死里逃生时，目光逐渐聚焦到线粒体身上。毕竟，线粒体不仅是细胞的能量工厂，更是细胞凋亡的指挥中心。近日，美国新泽西州立大学的Christina Glytsou团队发表于Science Advances的一篇论文揭示，耐药性AML细胞中OPA1蛋白表达上调，而该蛋白的过度表达会导致线粒体的独有结构——线粒体嵴的结构发生改变，变得更加紧缩。这些线粒体嵴如同蛛网一般，将大量细胞色素c等死亡诱导因子“捕获”，从而逃避凋亡。研究证实，使用特异性小分子抑制剂靶向OPA1，能够有效逆转维奈克拉的耐药性，并改变肿瘤细胞的代谢特性。研究者们首先是在临床样本中找到了关键线索。他们通过对AML患者骨髓细胞的单细胞测序分析，他们发现，与健康的造血细胞相比，AML细胞中的OPA1基因表达量显著升高。在对维奈克拉或MCL-1抑制剂耐药的细胞系中，也观察到了同样的现象。这仅仅是巧合吗？OPA1的升高究竟带来了什么变化？要知道，OPA1是调控线粒体嵴形态的关键蛋白；而嵴，是线粒体内膜折叠形成的结构，更是能量代谢和凋亡信号传导的关键场所。通过高分辨电子显微镜，研究者们清晰地看到，耐药AML细胞的线粒体嵴变得更窄、更密、更紧实。这种结构上的加固，把原本易于释放的“死亡信号”，例如细胞色素c，牢牢锁在了嵴膜内部，使得维奈克拉发出的凋亡指令难以有效执行。对来自复发或难治性AML患者的样本分析则进一步证实，线粒体嵴的紧缩是临床耐药的一个普遍特征。为验证OPA1的功能，研究团队使用CRISPR-Cas9技术在AML细胞中敲除了OPA1基因。结果显示，OPA1缺失显著增强了AML细胞对维奈克拉的敏感性，使IC50值大幅降低。即使在已建立耐药的细胞中，OPA1敲除也能恢复其对药物的反应。在小鼠模型中，OPA1缺失与维奈克拉联用显著延长了白血病小鼠的生存期。基于遗传学证据，研究团队评估了两种小分子OPA1抑制剂——MYLS22和其升级版Opitor-0的治疗潜力。电镜分析显示，MYLS22处理可引起与基因敲除类似的线粒体嵴形态改变，使嵴结构变得宽松。在多种AML细胞系和患者来源的异种移植（PDX）模型中，MYLS22或Opitor-0与维奈克拉联用时，线粒体嵴结构重塑效应促进了细胞色素c的释放，从而有效启动凋亡程序，表现出强大的协同抗白血病效应。更重要的是，这种联合治疗对正常造血干细胞影响较小，显示出良好的安全性。在移植了人类AML细胞的小鼠模型中，联合治疗显著延长了生存期，即使是对于携带TP53突变（通常与极差预后和维奈克拉耐药相关）的难治模型，也能有效降低白血病负荷。除了直接促进凋亡，研究者们还深入挖掘了OPA1抑制后引发的连锁反应。他们发现，抑制OPA1会损害线粒体的呼吸功能，迫使AML细胞在能量代谢上另寻他路。通过代谢组学和同位素标记追踪，他们捕捉到一个关键转变，即肿瘤细胞变得极度依赖谷氨酰胺。这些细胞通过增加谷氨酰胺摄取和还原性羧化途径来维持三羧酸循环和抗氧化防御。研究者们认为，这一代谢弱点可被进一步利用。于是，他们尝试在谷氨酰胺剥夺条件下或使用谷氨酰胺酶抑制剂CB-839处理，结果显示OPA1被抑制的AML细胞表现出更明显的生长抑制。此外，研究还发现OPA1抑制会激活ATF4介导的整合应激反应，上调多个与铁死亡相关的基因，包括CHAC1。实验证实，MYLS22预处理可增强铁死亡诱导剂Erastin的功效，提高线粒体脂质过氧化水平。这表明诱导铁死亡可能是与OPA1抑制剂联用的又一潜在策略。本研究系统性地揭示了OPA1介导的线粒体结构重塑在AML耐药中的关键作用。从临床观察到机制探索，再到治疗验证，研究证实靶向OPA1能有效逆转维奈克拉耐药。MYLS22和Opitor-0作为特异性OPA1抑制剂，与维奈克拉联用展现出协同抗白血病活性，且对不同遗传背景的AML均有效，为高危患者（如TP53突变型）提供了新的治疗可能。研究还揭示了OPA1抑制后的代谢脆弱点和铁死亡敏感性，为设计多靶点联合治疗方案提供了新思路。未来，OPA1抑制剂有望成为克服AML耐药的重要武器，为患者带来新的希望。参考文献：[1]Berens EB, Khou S, Huang ET, Hoffman A, Johnson B, Kirchberger N, Sivagnanam S, Calistri NL, Derrick DS, Liby TA, McLean IC, Alanizi AA, Ozmen F, Ozmen TY, Mills GB, Hwang ES, Schedin P, Gonzalez Velozo H, Werb Z, Heiser LM, Coussens LM. Neoplastic Immune Mimicry Potentiates Breast Tumor Progression. Cancer Res. 2025 Oct 23. doi: 10.1158/0008-5472.CAN-25-0985. Epub ahead of print. PMID: 41129726.本文作者丨张艾迪

基因疗法临床结果

100 项与 MYLS-22 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
急性髓性白血病	临床前	美国	Rutgers State University of New Jersey	2025-10-15
肺腺癌	临床前	日本	Wakayama Medical University	2023-04-05
肺腺癌	临床前	意大利	University of Padua	2023-04-05
肺腺癌	临床前	意大利	Veneto Institute of Molecular Medicine	2023-04-05